This invention relates to phosphoric acid derivatives. More particularly, this invention relates to
1) phosphoric acid derivatives of the formula (I) 
wherein all symbols are the same meaning as hereinafter defined and non-toxic salts thereof,
2) processes for the preparation thereof, and
3) pharmaceutical compositions containing them as active ingredient.
Tumor necrosis factor a (TNFxcex1) was discovered found as a factor that induces tumor hemorrhagic necrosis. TNFxcex1 is produced by macrophages as well as various other cells, including lymphocytes (CD4+ T cells, CD8+ T cells, B cells), neutrophils, stellate cells, endothelial cells and smooth muscle cells. TNFxcex1 showed various physiological activities by affecting various cells. TNFxcex1 is believed to play an important role especially in inflammatory reactions as a biophylactic response. Macrophages and neutrophils are deeply involved in development and progress of inflammatory reaction. TNFxcex1 stimulates vulnerary activities of macrophages and increases release of inflammatory cytokines, including TNFxcex1, interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) etc. Also TNFxcex1 is associated with activation of neutrophils such as phagocytosis, degranulation, chemotaxis and expression of adhesion molecules and enhances production of platelet activating factor and active oxygen by neutrophils. TNFxcex1 stimulates growth, induction of interleukin-2 (IL-2) receptor and production of interferon xcex3 and colony-stimulating factor in T cells, which play an important role in immune response. Besides TNFxcex1 provides help to B lymphocytes for antibody production and cell division.
It is reported below that TNFxcex1 is involved in variety of diseases. p0 (1) It may be a cause of fulminant hepatitis that TNFxcex1 levels in serum of the patients with fulminant hepatitis were higher than that of the patients with the severe form of acute hepatitis [H. Iwai et. al., Crit. Care. Med., 26, 873 (1998)].
(2) TNFxcex1 contents in intestinal mucosa from inflammatory bowel disease were markedly increased [Z. Kmiec, Arch. Immunol. Ther. Exp., 4, 143 (1998)].
(3) In the patients with Crohn""s disease, anti TNFxcex1 antibody was effective endoscopically [D. W. Hommes et. al., Haemostasis, 27, 269 (1997)].
(4) There was a correlation between TNFxcex1 and glucose level in serum of the patients with insulin dependent diabetes [M. Muc-Wierzgon et. al., Pol. Arch. Med. Wewn., 97, 426 (1998)].
(5) In the patients with interstitial pneumonia, ability to produce TNFxcex1 by alveolar macrophages are enhanced than in controls [J. Ancochea et. al., Arch. Bronconeumol., 33, 335 (1997)].
(6) Anti-TNFxcex1 antibody was effective on experimental autoimmune uveitis in mice [G. Sartani et. al., Invest. Ophthalmol. Vis. Sci., 37, 2211 (1996)].
(7) Thalidomide, which is a TNFxcex1 production inhibitor, diminished mechanical allodynia and thermal hyperalgesia in bennet model and improved the pathologic vascular injury [C. Sommer et. al., Pain, 74, 83 (1998)].
(8) Thalidomide was effective for diarrhea and weight loss in HIV patients [D. Sharpstone et. al., Gastroenterol, 112, 1823 (1997)].
(9) Anti-TNFxcex1 antibody reduced infarct volume in middle cerebral artery ischemia-reperfusion model [G. Yang et. al., Neuroreport, 9, 2131 (1998)].
Therefore inhibitors of TNFxcex1 production may be considered useful as preventives and/or remedies of various diseases induced by inflammatory cytokines including TNFxcex1. In view of physiological activity and involvement of TNFxcex1 with diseases, these inhibitors may be useful for rheumatoid arthritis, ulcerative colitis, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.
For example, it is disclosed in JP kokai 55-118494 that the phosphorylcholine type compound of the formula (A) 
wherein R1A and R2A are the same or different to represent hydrogen atom, optionally substituted by alkyl, alkenyl, aralkyl, aryl, acyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonyl, alkoxycarbonylaminoalkyl, carbamoyl, thiocarbamoyl, or heterocyclic ring, R3A and R5A are the same or different to represent hydrogen atom, carboxyl, optionally substituted by alkyl, alkenyl, aralkyl, aryl, alkoxycarbonyl, or heterocyclic ring, R4A represents hydrogen atom, alkyl, alkenyl, aralkyl, or aryl etc., AA represents oxygen atom, sulfur atom, or xe2x80x94NR8Axe2x80x94 (wherein R8A repersents hydrogen atom, etc.), R6A is the same or different to represent hydrogen atom, or optionally substituted by alkyl, aralkyl, R7A represents alkyl, aralkyl, X1A and X2A represent oxygen atom or sulfur atom, IA and mA each, is 0, 1 or 2, and nA is 2 or 3 is useful as antitumor agent.
It is disclosed in WO 96/22966 that the compound of the formula (B) 
wherein XB represents xe2x80x94COOH, xe2x80x94Pxe2x88x92O3H, xe2x80x94SO2R5B, xe2x80x94SO3H, xe2x80x94OPxe2x88x92O3H, xe2x80x94COOR4B or xe2x80x94CON(R4B)2, YB repersents xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, or xe2x80x94PO2xe2x80x94, R1B represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl etc., R2B represents hydrogen atom, aryl, alkyl, alkenyl, alkynyl, or cycloalkyl etc., R3B represents alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl etc., or R2B and R3B, taken together with the atom to which they are attached, represent heterocyclyl, R4B represents aryl, alkyl, or cycloalkyl etc., and nB is 0, 1 or 2 is useful as a cell adhesion inhibitor.
Energetic investigations have been carried out to find new compounds having TNFxcex1 production inhibitory activity. As a result, the present inventor have found that these aims may be accomplished by a phosphoric acid derivatives of the formula (I).
The phosphoric acid derivatives of the formula (I) have not been known as TNFxcex1 production inhibitor at all.
The present invention relates to
1) Phosphoric acid derivatives of the formula (I) 
wherein R1 is
(1) C1-20 alkyl,
(2) C1-20 alkyl which one carbon atom is replaced by an oxygen atom, a sulfur atom, xe2x80x94S(O)xe2x80x94 or S(O)2xe2x80x94 (with the proviso that, a carbon atom which attached with E is not replaced by these groups),
(3) C2-20 alkenyl,
(4) C2-20 alkynyl,
(5) Cyc1 (wherein Cyc1 is C5-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom),
(6) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl substituted by Cyc1 (wherein all symbols are the same meaning as hereinbefore defined), Cyc1 may be substituted by one or more substituents selected from the following (a)-(r):
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) nitro,
(d) halogen atom,
(e) trifluoromethyl,
(f) trifluoromethyloxy,
(g) hydroxy,
(h) cyano,
(i) NR10R11 (wherein R10 and R11 each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 hydroxyalkyl, C2-5 acyl or C1-8 alkylsulfonyl),
(j) COOR20 (wherein R20 is a hydrogen atom or C1-4 alkyl),
(k) CONR30R31 (wherein R30 and R31 each, independently, is a hydrogen atom or C1-4 alkyl),
(l) xe2x80x94S(O)mxe2x80x94R32 (wherein m is 0, 1 or 2, R32 is 1-8 alkyl or C1-8 alkyl substituted by C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined) or CONR30R31 (wherein R30 and R31 each, independently, is a hydrogen atom or C1-4 alkyl)),
(m) xe2x80x94Oxe2x80x94Cyc2 (wherein Cyc2 is C3-8 cycloalkyl or phenyl),
(n) xe2x80x94Sxe2x80x94Cyc2 (wherein Cyc2 is the same meaning as hereinbefore defined),
(o) C1-8alkyl substituted by one substituent selected from C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined), CONR30R31 (wherein R30 and R31 are the same meaning as hereinbefore defined), phenyl or hydroxy.
(p) C1-8alkoxy substituted by one substituent selected from C1-8 alkoxy, COOR20 (wherein R20 is the same meaning as hereinbefore defined), CONR30R31 (wherein R30 and R31 are the same meaning as hereinbefore defined), phenyl or hydroxy,
(q) C3-15 membered mono-, bi- or tricarbocyclic ring,
(r) 5-15 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
E is
(a) xe2x80x94NR7COxe2x80x94,
(b) xe2x80x94NR7SO2xe2x80x94,
(c) xe2x80x94NR7CONR8xe2x80x94,
(d) xe2x80x94NR7COOxe2x80x94,
(e) xe2x80x94CONR7xe2x80x94,
(f) xe2x80x94NR7CSxe2x80x94,
(g) xe2x80x94NR7CSNR8xe2x80x94,
(h) xe2x80x94NR7CSxe2x80x94Oxe2x80x94,
(i) xe2x80x94CSNR7xe2x80x94 or
(j) xe2x80x94NR7xe2x80x94 (wherein R7 and R8 each, independently, is a hydrogen or C1-4 alkyl), A ring is C3-15 membered mono-, bi- or tricarbocyclic ring or 5-15 membered mono-, bi- or trycyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or one sulfur atom,
R2 is the same meaning as hereinbefore defined substituents (a)-(r), R3 and R4 
i) each, independently, is a hydrogen atom, C1-8 alkyl, C1-8 alkoxy, C1-8 hydroxyalkyl or phenyl, or
ii) taken together represents C2-6 alkylene, or
iii) one of R3 or R4, taken together with R2, represent C1-5 alkylene, and the other one is a hydrogen atom, C1-8alkyl or C1-8alkoxy,
n is an integer of 0, 1 or more,
R5 and R6 each, independently, is a hydrogen atom, C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by cyano or C1-4 alkyl substituted by trihalomethyl,
Y and Z each, independently, is an oxygen atom or a sulfur atom,
xe2x80x83with the proviso that,
(1) when n is 2 or more integer, then R2 is the same or different,
(2) when R1 and R2 represent contains a sulfur atom, then Y is an oxygen atom, and R1 and R2 do not represent contains a sulfur atom at the same time or a non-toxic salt thereof,
2) processes for the preparation thereof, and
3) pharmaceutical composition containing them as active ingredient.
In the present specification, C1-4 alkyl means methyl, ethyl, propyl, butyl and isomers thereof.
In the present specification, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the present specification, C1-20 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and isomers thereof.
In the present specification, C2-20 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icosenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, undecadienyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, nonadecadienyl, icosadienyl, hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl, undecatrienyl, dodecatrienyl, tridecatrienyl, tetradecatrienyl, pentadecatrienyl, hexadecatrienyl, heptadecatrienyl, octadecatrienyl, nonadecatrienyl, icosatrienyl and isomers thereof.
In the present specification, C2-20 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, icosynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl, decadiynyl, undecadiynyl, dodecadiynyl, tridecadiynyl, tetradecadiynyl, pentadecadiynyl, hexadecadiynyl, heptadecadiynyl, octadecadiynyl, nonadecadiynyl, icosadiynyl, hexatriynyl, heptatriynyl, octatriynyl, nonatriynyl, decatriynyl, undecatriynyl, dodecatriynyl, tridecatriynyl, tetradecatriynyl, pentadecatriynyl, hexadecatriynyl, heptadecatriynyl, octadecatriynyl, nonadecatriynyl, icosatriynyl and isomers thereof.
In the present specification, C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
In the present specification, C1-5 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene and isomers thereof.
In the present specification, C2-6 alkynene means ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomers thereof.
In the present specification, C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the present specification, a halogen atom is chlorine, bromine, fluorine or iodine.
In the present specification, C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, C1-8 hydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl and isomers thereof.
In the present specification, C1-4 alkyl substituted by phenyl means phenylmethyl, phenylethyl, phenylpropyl and phenylbutyl.
In the present specification, C1-4 alkyl substituted by cyano means cyanomrethyl, cyanoethyl, cyanopropyl and cyanobutyl.
In the present specification, C1-4 alkyl substituted by trihalomethyl means methyl, ethyl, propyl or butyl substituted by trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.
In the present specification, C3-15 membered mono-, bi- or tricarbocyclic ring includes a C3-15 membered mono-, bi- or tricarbocyclic aryl, partially saturated or fully saturated one; for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene, adamantane etc.
In the present specification, 5-15 membered mono-, bi- or tricyclic heterocyclic ring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur includes 5-15 membered mono-, bi- or tricyclic heterocyclic aryl, partially saturated or fully saturated one containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur.
Above-mentioned 5-15 membered mono-, bi- or tricyclic heterocyclic aryl containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur represents pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiin (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, carbazole, acridine, etc.
Above-mentioned 5-15 membered mono-, bi- or tricyclic heterocyclic ring which is partially saturated or fully saturated, containing 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur represents pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiine (dihydrothiopyran), tetrahydrothiine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indoloxazepine, indolotetrahydrooxazepine, indolooxadiazepine, indolotetrahydrooxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indoloazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane, dioxane, dioxazine, etc.
In the present invention, as may be easily understood by those skilled n the art, the symbol:

indicates that the substituent attached thereto is in front of the sheet (xcex2-position), unless otherwise specified, the symbol:

indicates that the substituent attached thereto is behind the sheet (xcex1-position), unless otherwise specified, the symbol:

indicates that the substituent attached thereto is xcex2-position or xcex1-position (though it is single isomer that it attached thereto is either xcex2-position or xcex1-position, the structure is not determined), the symbol:

indicates the mixture of the compounds that the substituent attached thereto is xcex2-position and xcex1-position.
In the formula (I), ring A is preferably C3-15 membered mono-, bi- or tricarbocyclic ring, more preferably C3-7 membered monocarbocyclic ring, even more preferably benzene, cyclopentane, cyclohexane or cycloheptane, most preferably benzene.
In the formula (I), R3 and R4 are preferably that each, independently, is hydrogen atom or C1-8 alkyl, more preferably C1-4 alkyl, and most preferably that each, independently, is hydrogen atom and methyl.
In the formula (I), when one of R3 and R4 is a hydrogen atom and the ther is not a hydrogen atom, then the former is preferably attached to the xcex1-position (behind the sheet), and the latter is preferably attached to the xcex2-position (in front of the sheet).
In the formula (I), E is preferably xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONR8xe2x80x94, or xe2x80x94NR7COOxe2x80x94, more preferably xe2x80x94NR7COxe2x80x94 or xe2x80x94NR7COOxe2x80x94 (wherein all symbols are the same meaning as hereinbefore defined), and most preferably xe2x80x94NHCOxe2x80x94 or xe2x80x94NHCOOxe2x80x94.
In the formula (I), E may be attached xcex1-position or xcex2-position, preferably xcex2-position (in front of the sheet).
In the formula (I), R1 is preferably C1-20 alkyl, more preferably C5-10 alkyl, and most preferably heptyl.
In the formula (I), R2 is prepreably C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio or COOR20 (R20 is the same meaning as hereinbefore defined), more preferably C1-4 alkoxy, C1-4 alkylthio, COOR200 (R200 is C1-4alkyl), and most preferably methoxy, isopropyloxy, methylthio or methoxycarbonyl.
In the formula (I), when benzene ring is substituted by R2, then the position of substitution is preferably 3-position.
In the formula (I), n is preferably 0-5, and more preferably 0-2.
Concretely, the compounds that hereinafter described in the examples and the compounds in the following tables 1-89 are preferably. Besides, in the following tables, the numbers described before each group represent the position of substitution, Me is methyl group, Et is ethyl group, Ph is phenyl group and Py is pyridyl group.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkoxy, alkylthio, alkenyl, alkynyl and alkylene include straight and branched isomers. Isomers in the double bonds, rings, fused rings (E, Z, cis, trans isomers), isomers generated by the existence of asymmetric carbon atom(s) (R, S isomers, xcex1, xcex2 isomers, enantiomers, diastereomers), optically active isomers having optically rotatory power (D, L, d, I isomers, +, xe2x88x92 isomers), polar isomers separated by chromatography (more polar, less polar isomers), equilibrium compounds, arbitrary ratios of these compounds, racemic mixtures are all included in the present invention. Optically active isomers of formula (I) in the present invention may be obtained by general methods of optically separation (for example, separation by gas chromatography or high performance liquid chromatography, separation by crystallization as diastereomeric salts or clathrates, separation by prior crystallization etc.) or may be prepared by general methods of asymmetric synthesis.
[Salt]
The compounds of formula (I) of the present invention may be converted into the corresponding salts by conventional method. Non-toxic and water-soluble salts are preferred. Suitable salts, for example, include: salts of alkali metals (e.g. potassium, sodium, etc.), salts of alkaline earth metals (e.g. calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.). Salts of alkali metals are preferably.
The compounds of formula (I) of the present invention and salts thereof may be converted into the corresponding hydrates by conventional means.
[Processes for the Preparation of the Compound of the Present Invention]
The compounds of formula (I) of the present invention may be prepared by following, described in example or known methods.
(1) In the compounds of the formula (I), the compounds in which all of R1 and R2 do not contain carboxyl, hydroxy or amino, and all of R3 and R4 do not contain hydroxy, that is the compounds of the formula (IA) 
wherein R1a and R2a are the same meaning as R1 and R2 respectively, provided that, when at least one of R1 and R2 represent contain carboxyl, hydroxy or amino, then each carboxyl, hydroxy or amino is protected by protective group, R3a and R4a are the same meaning as R3 and R4 respectively, provided that, when at least one of R3 and R4 represent contain hydroxy, then the hydroxy is protected by protective group, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by following method (1-1), (1-2) or (1-3).
(1-1) In the compounds of the formula (IA), the compounds in which all of R5 and R6 do not represent a hydrogen atom, that is the compounds of the formula (IA-1) 
wherein R50 and R60 each, independently, is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by trihalomethyl or C1-4 alkyl substituted by cyano,
xe2x80x83may be prepared by reacting the formula (X-1) 
wherein all symbols are the same meaning as hereinbefore defined
xe2x80x83with the compound of the formula (X-2) 
wherein X is a halogen atom or hydroxy, and the other symbols are the same meaning as hereinbefore defined.
The reaction of the compound of the formula (X-1) with the compound of the formula (X-2) is known per se, for example, when X is a halogen atom, then the reaction may be carried out in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine , etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C. When X is hydroxy, then the reaction may be carried out in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) in an inert organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetone, benzene, toluene, etc. ), at a temperature of from 0xc2x0 C. to 60xc2x0 C.
In the compounds of the formula (IA-1), the compounds in which all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, that is the compounds of the formula (IA-1-X) 
wherein R1a-x and R2a-x are the same meaning as R1a and R2a, with the proviso that, all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 and xe2x80x94S(O)xe2x80x94, and other symbols are the same meaning as hereinbefore defined
may be prepared by reacting the compound of the formula (X-1-X), 
wherein all symbols are the same meaning as hereinbefore defined
which in the compound of the formula (X-1), all of R1a and R2a do not contain xe2x80x94Sxe2x80x94 and xe2x80x94S(O)xe2x80x94 with the compound of the formula (X-3) 
wherein R12 and R13 each, independently, is C1-8 alkyl, and the other symbols are the same meaning as hereinbefore defined
followed by oxidation.
The reaction of the compound of the formula (X-1-X) with the compound of the formula (X-3) may be carried out in the presence of tetrazole in an inert organic solvent (acetonitrile, tetrahydrofuran, diethyl ether, methylene chloride, chloroform, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Above-mentioned oxidation may be carried out in a solvent (acetonitrile, methylene chloride, water, etc.) in the presence of oxidant (3-chloroperoxybenzoic acid, iodine, hydrogen peroxide, t-butyl hydroperoxide, 3H-1,2-benzothiol-3-one 1,1-dioxide, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(1-2) In the compounds of the formula (IA), in which R5 and R6 are a hydrogen atom, that is the compounds of the formula (IA-2) 
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid.
The deprotection reaction of the protective group for phosphoric acid is known per se, for example,
(a) Elimination of C1-2 alkyl may be carried out in an organic solvent (chloroform, etc.) in the presence of trimethylsilyl halide (trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide, etc.) in the presence or absence of alkali metal iodide (sodium iodide or potassium iodide, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(b) Elimination of phenyl may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol or tetrahydrofuran, etc.) or without a solvent in the presence of catalyst (platinum dioxide, etc.), and in the presence or absence of organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) for 24 hours to 3 days at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(c) Elimination of benzyl may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol, tetrahydrofuran, pyridine or acetic acid, etc.) in the presence of catalyst (palladium-carbon, palladium black or palladium hydroxide, etc.) at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(d) Elimination of 2,2,2-trichloroethyl may be carried out in an organic solvent (methanol, ethanol or tetrahydrofuran, etc.) or without a solvent, using zinc powder and organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) at a temperature of from 0xc2x0 C. to 50xc2x0 C.
The compounds in which R1a represent contains alkenyl or alkynyl ay be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (d).
The compound in which R1a dose not contain alkenyl or alkynyl may be prepared by subjecting to a deprotection reaction that above-mentioned method from (a) to (d). With the proviso that, when Cyc1 and/or A ring represented by R1 is carbocyclic aryl or heterocyclic aryl, then the compound may be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (c)xcx9c(d), and when nitro is containing in R1 or R2, then the compound may be prepared by subjecting to a deprotection reaction that above-mentioned method (a) or (d).
(1-3) In the compounds of the formula (IA), the compounds in which one of R5 or R6 is a hydrogen atom and the other is not a hydrogen atom, that is the compounds of the formula (IA-3) 
wherein one of R51 or R61 is a hydrogen atom and the other is C1-8 alkyl, phenyl, C1-4 alkyl substituted by phenyl, C1-4 alkyl substituted by trihalomethyl or C1-4 alkyl substituted by cyano, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by following method (1-3-a) or (1-3-b).
(1-3-a) The compound of the formula (IA-3) may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid of the compound of the formula (IA-1) hereinbefore described.
This deprotection reaction of the protective group for phosphoric acid may be carried out under some condition hereinafter described, and depends on the protective group, for example,
(1) in organic solvent (diethyl ether, methanol, tetrahydrofuran or dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide or potassium hydroxide, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.,
(2) in organic solvent (tetrahydrofuran or pyridine, etc.), using t-butylamine or tetrabutylammonium hydroxide at a temperature of from 0xc2x0 C. to 100xc2x0 C., or
(3) in organic solvent (2-ethoxyethanol or acetone, etc.), using lithium halide (lithium chloride or lithium bromide, etc.) under reflux condition.
(1-3-b) In the compounds of formula (IA-3), the compounds in which one of R51 or R61 is a hydrogen and the other is phenyl, R1a does not contain alkenyl or alkynyl, that is the compounds of the formula (IA-3-B) 
wherein Ph is phenyl, R1a-b is the same meaning as R1a, provided that, R1a does not contain alkenyl or alkynyl, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by subjecting to a deprotection reaction of the protective group for phosphoric acid of the compound of the formula (IA-1-B) 
wherein all symbols are the same meaning as hereinbefore defined.
The elimination reaction of protective group for phosphoric acid may be carried out under an atmosphere of hydrogen, in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) or without a solvent in the presence of catalyst (platinum dioxide, etc.), in the presence or absence of organic acid (acetic acid, etc.) or inorganic acid (hydrochloric acid, etc.) for 1-3 hours at a temperature of from 0xc2x0 C. to 50xc2x0 C.
(I-4) In the compound of formula (IA), the compounds in which one of R1a or R2a represent contains xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, that is the compounds of the formula (IA-4) 
wherein R1a-c and R2a-c are the same meaning as R1a and R2a, respectively, provided that, one of R1a or R2a represent contains xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, and the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by oxidation among the compound of formula (IA-1), (IA-2) or (IA-3) hereinbefore described, the compounds in which one of R1a or R2a represent contains xe2x80x94Sxe2x80x94, that is the compounds of the formula (IA-5). 
wherein R1a-d and R2a-d are the same meaning as R1a and R2a, respectively, provided that, one of R1a or R2a represent contains xe2x80x94Sxe2x80x94, and the other symbols are the same meaning as hereinbefore defined.
The oxidation is known per se, and may be carried out, for example, in suitable organic solvent (methylene chloride, chloroform, benzene, hexane, t-butylalcohol, etc.) in the presence of oxidant (hydrogen peroxide, sodium periodate, acyl nitrites, sodium perborate, a peroxide (for example, 3-chloroperbenzoic acid or peroxiacetic acid, etc.), potassium peroxomonosulfate, potassium permanganate, chromic acid, etc.) at a temperature of from 20xc2x0 C. to 60xc2x0 C.
Above-mentioned the compounds of the formula (X-1) may be prepared by the method described in the following reaction scheme 1.
In the scheme, all symbols are the same meaning as hereinbefore defined, and all reaction may be carried out as the methods hereinafter described in (1A-1-a), (1A-1-b), (1A-1-c), (1A-1-d-1), (1A-1-d-2), (1A-1-e) and (1A-1-f). 
In the compounds of the formula (IA-1), the compounds in which E is not xe2x80x94CONR7xe2x80x94 or xe2x80x94CSNR7xe2x80x94, i.e. xe2x80x94NR7COxe2x80x94, xe2x80x94NR7SO2xe2x80x94, xe2x80x94NR7CONR8xe2x80x94, xe2x80x94NR7COOxe2x80x94, xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSNR8xe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7xe2x80x94 may be prepared by the method described in the following (1A-1-a), (1A-1-b), (1A-1-c), (1A-1-d-1), (1A-1-d-2), (1A-1-e) or (1A-1-f.
(1A-1-a) In the compounds of the formula (IA-1), the compounds in which E is xe2x80x94NR7COxe2x80x94, that is the compounds of the formula (IA-1-A) 
wherein E1 is xe2x80x94NR7COxe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by amidation of the compound of the formula (X-5) 
wherein all symbols are the same meaning as hereinbefore defined with the compound of the formula (X-6A)
R1axe2x80x94COOHxe2x80x83xe2x80x83(X-6A)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined.
The amidation is known per se and can be carried out by methods for example:
1) using an acid halide,
2) using a mixed acid anhydride,
3) using a condensing agent (EDC, DCC, etc.), etc.
These methods are explained as follows.
1) The method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (oxalyl chloride or thionyl chloride, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding amine in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Besides, the reaction may be carried out in an organic solvent (dioxane, tetrahydrofuran, etc.), using aqueous solution of hydroxide or carbonate of alkali metal (an aqueous solution of sodium bicarbonate, an aqueous solution of sodium hydroxide, etc.) with acid halide at a temperature of from 0xc2x0 C. to 40xc2x0 C.
2) The method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (pivaloyl chloride, tosyl chloride or mesyl chloride, etc.) or an acid derivative (ethyl chloroformate or isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) or without a solvent at a temperature of from 0xc2x0 C. to 40xc2x0 C., and then by reacting the mixture of acid anhydride obtained with a corresponding amine in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.
3) The method using a condensing agent may be carried out, for example, by reacting a carboxylic acid with a corresponding amine using a condensing agent (1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI) or 2-chloro-1-methylpyridinium iodide, etc.) in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, dimethyl formamide, diethyl ether or tetrahydrofuran, etc.) or without a solvent, in the presence or absence of 1-hydroxybenztriazole (HOBt) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
These reactions 1), 2) and 3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (argon or nitrogen , etc.) under anhydrous conditions.
(1A-1-b) In the compounds of the formula (IA-1), the compounds in which E is xe2x80x94NR7COOxe2x80x94, that is the compounds of the formula (IA-1-B) 
wherein E2 is xe2x80x94NR7COOxe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reaction for forming urethane of the compounds of the formula (X-5) with the compounds of the formula (X-6B)
R1axe2x80x94OCOxe2x80x94X1xe2x80x83xe2x80x83(X-6B)
wherein X1 is a halogen atom, the other symbols are the same meaning as hereinbefore defined.
The reaction for forming urethane of the compounds of (X-5) with the compounds of the formula (X-6B) may be carried out as the same methods which above-mentioned 1) using an acid halide of amidation.
(1A-1-c) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7SO2xe2x80x94, that is the compounds of the formula (IA-1-C) 
wherein E3 is xe2x80x94NR7SO2xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by sulfonamidation of the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6C)
R1axe2x80x94SO2Clxe2x80x83xe2x80x83(X-6C)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined.
The sulfonamidation is known per se and can be carried out, for example, using sulfonyl halide in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine, etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(1A-1-d-1) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CONR8xe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, that is the compounds of the formula (IA-1-D-1) 
wherein E4 is xe2x80x94NR7CONR8xe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6D-A)
R1axe2x80x94NHR8xe2x80x83xe2x80x83(X-6D-A)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined and the compound of the formula (X-6D-B) 
wherein T is an oxygen atom or a sulfur atom.
The reaction using the compounds of the formulae (X-5), (X-6D-A) and (X(-6D-B) can be carried out by known method, for example, in an organic solvent (N,N-dimethylformamide, methylene chloride or tetrahydrofuran, etc.) in the presence or absence of an amine (triethylamine, pyridine, dimethylaniline or dimethylaminopyridine, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C.
(1A-1-d-2) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CONR8xe2x80x94, that is the compounds of the formula (IA-1-D-2) 
wherein E44 is xe2x80x94NR7CONR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6D-C)
R1axe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(X-6D-C)
xe2x80x83wherein all symbols are the same meaning as hereinbefore defined or the compounds of the formula (X-6D-D) 
wherein X2 is a halogen atom, the other symbols are the same meaning as hereinbefore defined.
The reaction of the compounds of the formula (X-5) and (X-6D-C), or the reaction of the compounds of the formula (X-5) and (X-6D-D) are known per se, and can be carried out, for example, in an organic solvent (acetone, chloroform, methylene chloride, benxene or tetrahydrofuran, etc.) in the presence or absence of a tertiary amine (triethylamine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C., or as the same methods which above-mentioned 1) using an acid halide of amidation.
(1A-1-e) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7xe2x80x94, that is the compounds of the formula (IA-1-E) 
wherein E5 is xe2x80x94NR7xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (X-5) hereinbefore described with the compounds of the formula (X-6E)
X3xe2x80x94R1axe2x80x83xe2x80x83(X-6E)
xe2x80x83wherein X3 is a halogen atom or hydroxy, the other symbols are the same meaning as hereinbefore defined.
The reaction of the compounds of the formula (X-5) with the compounds of the formula (X-6E) is N-alkylation or corresponding one. For example, when X3 is a halogen atom, then the reaction may be carded out in an organic solvent (N,N-dimethylformamide or tetrahydrofuran, etc.) in the presence of a base (sodium hydride, butyl lithium, lithium diisopropylamide, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C. And when X3 is hydroxy, then the reaction may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetone, benzene, toluene, etc.) in the presence of an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) at a temperature of from 0xc2x0 C. to 60xc2x0 C.
(1A-1-f) In the compounds of the formula (I), the compounds in which E is xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, that is the compounds of the formula (IA-1-F) 
wherein E6 is xe2x80x94NR7CSxe2x80x94, xe2x80x94NR7CSxe2x80x94Oxe2x80x94 or xe2x80x94NR7CSNR8xe2x80x94, the other symbols are the same meaning as hereinbefore defined
xe2x80x83may be prepared by reacting the compounds of the formula (IA-1-A), (IA-1-B) or (IA-1-D-2) hereinbefore described, that is the compounds of the formula (IA-1-FF) 
wherein E66 is xe2x80x94NR7COxe2x80x94, xe2x80x94NR7COOxe2x80x94 or xe2x80x94NR7CONR8xe2x80x94, the other symbols are the ame meaning as hereinbefore defined
xe2x80x83with Lawesson""s Reagent of the formula (X-6F) 
The reaction using Lawesson""s Reagent is known per se, and can be carried out in an organic solvent (dioxane, benzene, toluene or xylene, etc.), using Lawesson""s reagent at a temperature of from 20xc2x0 C. to 150xc2x0 C. This reaction may be preferably carried out in an atmosphere of inert gas (argon or nitrogen, etc.) under anhydrous conditions.
(2) In the compounds of the formula (I), the compounds in which at least one of R1, R2, R3 or R4 represent contains carboxyl, hydroxy or amino, that is the compound of the formula (IB) 
wherein R1b, R2b, R3b or R4b is the same meaning as R1, R2, R3 or R4, respectively, provided that, at least one of them is a group containing carboxyl, hydroxy or amino
xe2x80x83may be prepared by the method described in the following (2-1), (2-2) or (2-3).
(2-1) In the compounds of the formula (IB), the compounds in which all of R5 and R6 is hydrogen atom, that is the compounds of the formula (IB-1) 
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-1), which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-1-Y) 
wherein R1a-y, R2a-y, R3a-y and R4a-y is the same meaning as R1a, R2a, R3a and R4a, provided that, at least one of them represent contains protected carboxyl, hydroxy or amino, the other symbols are the same meaning as hereinbefore defined.
Each deprotection reaction of protective group for phosphoric acid, carboxyl, hydroxy or amino is known well and means a comprehensive deprotection reaction easily understood by those skilled in the art, for example, alkali hydrolysis, deprotection reaction under acidic condition, deprotection reaction by hydrogenation or deprotection reaction of a group containing silyl. The desired compounds of the present invention can be easily prepared by these reactions.
Each deprotection reaction of protective group for phosphoric acid, carboxyl, hydroxy or amino are explained.
As should be easily understood by those skilled in the art, for example, methyl, ethyl, t-butyl and benzyl are included in the protective groups for carboxyl, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
For example, methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl and benzyl are included in the protective groups for hydroxy, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
For example, benzyloxycarbonyl, t-butoxycarbonyl and trifluoroacetyl are included in the protective groups for amino but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 may be used.
Deprotection reaction by alkali hydrolysis is known, for example, it is carried out in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Deprotection reaction under acidic conditions is known, for example, it is carried out in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.), in organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acid-acetic acid etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
Deprotection reaction by hydrogenation is known, for example, it is carried out in an inert solvent [ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (e.g. methanol, ethanol, etc.), benzene (e.g. benzene, toluene, etc.), ketone (e.g. acetone, methylethylketone, etc.), nitrile (e.g. acetonitrile etc.), amide (e.g. dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof], in the presence of hydrogenating catalyst (e.g. palladium-carbon, palladium black, palladium hydroxide, platinum dioxide, Raney-nickel, etc.) under normal atmosphere or suppressed atmosphere of hydrogen or in the presence of ammonium formate, at a temperature of from 0xc2x0 C. to 200xc2x0 C.
Deprotection reaction of silyl group is known, for example, it is carried out in a water-soluble organic solvent (tetrahydrofuran, acetonitrile, etc.), using tetrabutylammonium fluoride at a temperature of from 0xc2x0 C. to 40xc2x0 C.
(2-2) In the compounds of the formula (IB), the compound in which all of R5 and R6 are hydrogen atom, that is the compound of the formula (IB-2) 
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-2) hereinbefore described, which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-2-Y) 
xe2x80x83all symbols are the same meaning as hereinbefore defined.
The deprotection reaction is carried out as the same method hereinbefore described.
(2-3) In the compounds of the formula (IB), the compounds in which one of R5 and R6 is a hydrogen atom, and the other is not a hydrogen atom, that is the compounds of the formula (IB-3) 
wherein all symbols are the same meaning as hereinbefore defined may be prepared by subjecting to a deprotection reaction a compound, among the compound of the formula (IA-3) hereinbefore described, which contains at least one protected carboxyl, hydroxy or amino, i.e. the compound of the formula (IA-3-Y) 
xe2x80x83all symbols are the same meaning as hereinbefore defined.
The deprotection reaction is carried out as the same method hereinbefore described.
The compounds of the formula (X-5) may be prepared by the method described in the following reaction scheme 2.
In the scheme, X4 is a halogen atom or hydroxy, Q is a protective group for amino, the other symbols are the same meaning as hereinbefore defined. 
In the reaction scheme 2, the compounds in which R2a does not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, among the compound of the formula (X-10), that is the compounds of the formula (X-10-A) 
wherein R2a-a is the same meaning as R2a, provided that its does not contain xe2x80x94Sxe2x80x94 or xe2x80x94S(O)xe2x80x94, the other symbols are the same meaning as hereinbefore defined.
In the scheme, all symbols are the same meaning as hereinbefore defined. 
In each reaction described in the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions.
The starting materials and agents in the present invention are known per se (commercially available), or may be prepared by conventional method.
For example, in the compound of the formula (X-8), 2-amino-2-phenylethanol ((R)-(xe2x88x92)-2-phenyl glycinol, (S)-(+)-2-phenyl glycinol) is known as CAS No. 56613-80-0 (R form) and 20989-17-7(S form), and (1R,2S)-(+)-cis-1-amino-2-indanol and (1S,2R)-(xe2x88x92)-cis-1-amino-2-indanol are known as CAS No. 136030-00-7 and 126456-43-7, respectively.
Besides, 2-amino-2-phenyl-1,1-propanoethanol may be prepared according to the method described in the literature (Larry R. Kpepski et al., SYNTHESIS, 301,(1986)) from cyclobutanone as a starting material.
(1S,2R)-1-methyl-2-phenylethanol, (1R,2S)-1-methyl-2-phenylethanol, (1R,2R)-1-methyl-2-phenylethanol, and (1S,2S)-1-methyl-2-phenylethanol may be prepared according to the method described in the literatures ( K. Barry Sharpless et al., Tetrahedron Lett. 37(19), 3219(1996), von Vladimir Prelog et.al., Helvetica Chimca Acta 66(7), 2274,(1983), Christian R. Noe et.al., Monatsh Chem., 122(4), 283(1991)). 
Pharmacological Activities
Because of having a TNFxcex1 production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies of various diseases induced by inflammatory cytokines including TNFxcex1 (example for rheumatoid arthritis, ulcerative colitis, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.). It has been confirmed that the compounds of the present invention of the formula (I) possess a TNFxcex1 production inhibitory effect by the following experimental results.
(i) Measure of TNFxcex1 Production Inhibitory Activity
Measure of TNFxcex1 production inhibitory activity was prepared according to procedures described previously (Kazuo Ohuchi, SEIBUTSUKAGAKUJIKKENKOZA, 12, 707 (1994) Hirokawa, Tokyo). Female mice (BALB/c, 7 weeks) were injected with test compounds via intravenous administration and with LPS (100 xcexcg/mouse) (Bacto W. E. coli 055:B5; DIFCO Lab.) via in traperitoneal administration. At 90 minutes after LPS challenge, blood with heparin was obtained from abdominal aorta, and serum was stored at xe2x88x9280xc2x0 C. Serum level of TNFxcex1 was determined by mouse cytokine ELISA kit (Genzyme). Inhibition and 50% effective dose (ED50) of test compounds were calculated as 100% of the difference of serum level of TNFxcex1 between in control and in LPS. ED50 of some compounds produced by the following examples were 0.01-100 mg/kg. For examples, ED50 of (2R)-2-phenyl-2-(N-octanoylamino)ethylphosphate.2Na (the compound of example 8) was 2.6 mg/kg.
Toxicity
The toxicity of the compounds of the present invention is very low and therefore the compounds may be considered safe for pharmaceutical use.
Application for Pharmaceuticals
Because of having a TNFxcex1 production inhibitory effect, the compounds represented by general formula (I) are useful as preventives and/or remedies for rheumatoid arthritis, ulcerative colits, Crohn""s disease, hepatitis, sepsis, hemorrhagic shock, multiple sclerosis, cerebral infarction, diabetes, interstitial pneumonia, uveitis, pain, glomerulonephritis, HIV-associated diseases, cachexia, myocardial infarction, chronic heart failure, oral aphtha, Hansen""s disease, infection, etc.
For the purpose above described, the compounds of formula (I) of the present invention and non-toxic salts thereof, acid addition salts thereof and hydrates thereof may normally be administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered as inner solid compositions or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules etc. Capsules contain hard capsules and soft capsules.
In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate etc.), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, suspensions, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavouring agents, perfuming agents, preserving agents and buffer agents etc.
Injections for parenteral administration include solutions, suspensions and emulsions and solid injections which are dissolved or suspended in solvent when it is used. One or more active compound(s) is or are dissolved, suspended or emulsified in a solvent when such compositions are used. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution, plant oil, propylene glycol, polyethylene glycol and alcohol such as ethanol etc., and mixture thereof. Such compositions may comprise additional diluents such as stabilizing agent, assisting agents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark) etc.), suspending agents, emulsifying agents, dispersing agents, buffer agents, preserving agents etc. They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, ointments, endermic liniments, aerosols, spray compositions, suppositories and pessaries for vaginal administration etc. which comprise one or more of the active compound(s) and may be prepared by known methods.
Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.